STAT6 signature is not detectable in AD skin T-cells

Summary: IL-4 and IL-13 have unique and overlapping roles in different disease indications. IL-4 signals through both the type I (IL-4Ra & y chain), and type II receptors (IL-4Ra & IL-13Ra1). IL-13 however, only signals through the type II receptor. The type I receptor is primarily expressed by immune cells (B-cells, T-cells, monocytes) whereas the type II receptor is expressed by structural cells (keratinocytes, fibroblasts) and myeloid cells, but not by T-cells. AD was traditionally thought to be driven by the classical Th2 mechanism, in which IL-4 stimulates Th2 T-cells to produce IL-13. However, recent studies have failed to detect IL-4 expression in AD skin, while IL-13 is highly expressed by skin-infiltrating T-cells. In addition, the clinical data from IL-13 blocking antibodies lebrikizumab and tralokinumab, suggest a dominant role of IL-13 in AD. We hypothesized because T-cells only express the type I receptor, and thus can only be stimulated by IL-4 and not IL-13, a lack of STAT6 signature in these T-cells in AD skin, would further suggest that IL-4 is not stimulating T-cells, likely due to its low to no expression. A STAT6-signaling transcriptomic signature was created by stimulating PBMCs and keratinocytes with IL-13 in the presence or absence of lebrikizumab. This signature was screened against two AD skin RNA single cell datasets (Zhang et al, Allergy 2023 & Bangert et al Sci Immunol 2021). In both datasets, T-cells in AD skin showed no increase in STAT6 signature, as compared to healthy and Psoriasis skin T-cells. In AD skin, myeloid cells and keratinocytes showed an increase in STAT6 signature vs healthy skin and psoriasis lesions, suggesting that these cell types are stimulated by IL-13. In conclusion, our analysis showed no evidence for STAT6 signaling in AD skin T-cells, implying no local stimulation by IL-4. This finding further highlights the dominant role of IL-13, and not IL-4, in AD. Charlie Bridgewood¹, Lennart Roesner³, Ian Strickland¹, Elisabeth Hennes¹, JuanLuis Trincado¹, Bruna Oriol Tordera¹, Elisa Monzon Casanova¹, Ozge Uluckan¹, Thomas Werfel^{2, 3} 1. Almirall SA, Barcelona, CT, Spain. 2. Department of Dermatology and Allergy, Medizinische Hochschule Hannover, Hanover, Germany. 3. Cluster of Excellence RESIST, Medizinische Hochschule Hannover, Hanover, Germany. Translational Studies: Cell and Molecular Biology